Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics

ABSTRACT

Intermediate release nicotinic acid formulations having unique biopharmaceutical characteristics, which are suitable for oral administration once per day as a single dose preferably administered during the evening or at night for treating hyperlipidemia without causing drug-induced hepatotoxicity to such a level that requires the therapy to be discontinued, are disclosed. The intermediate nicotinic acid formulations can be administered as tablets in dosage strengths of, for example, 375 mg, 500 mg, 750 mg and 1000 mg. The 375 mg, 500 mg and 750 mg nicotinic acid tablets of the present invention have a dissolution curve similarity fit factor F 2  of at least about 79, and the 1000 mg nicotinic acid tablets of the present invention have a dissolution curve similarity fit factor F 2  of at least 44.

RELATED PATENT APPLICATIONS

[0001] This application for U.S. patent is a U.S.C., Title 35, §111(a)application, which is a continuation-in-part of U.S. patent applicationSer. No. 08/814,974 filed Mar. 6, 1997.

FIELD OF THE INVENTION

[0002] The present invention is directed to intermediate releasenicotinic acid formulations having unique biopharmaceuticalcharacteristics, which are useful for treating hyperlipidemia andmethods of treating hyperlipidemia employing such compositions. Anotheraspect of the present invention, the nicotinic acid formulations aresuitable for once a day dosing without causing drug-inducedhepatotoxicity to a level which would require the therapy to bediscontinued. More particularly, the present invention employs acomposition of nicotinic acid, derivatives and mixtures thereof, and aswelling agent to form an intermediate timed-release sustainingcomposition for nocturnal or evening dosing. Specifically, the presentinvention employs a composition of nicotinic acid and hydroxypropylmethylcellulose to treat hyperlipidemia in a once per day oral dosageform given during the evening hours that causes little if anyhepatotoxicity.

BACKGROUND

[0003] Nicotinic acid, 3-pyridinecarboxylic acid or niacin, is anantilipidemic agent that is marketed under, for example, the trade namesNicolar®, SloNiacin®, Nicobid® and Time Release Niacin®g. Nicotinic acidhas been used for many years in the treatment of lipidemic disorderssuch as hyperlipidemia, hypercholesterolemia and atherosclerosis. Thiscompound has long been known to exhibit the beneficial effects ofreducing total cholesterol, low density lipoproteins or “LDLcholesterol,” triglycerides and apolipoprotein a (Lp(a)) in the humanbody, while increasing desirable high density lipoproteins or “HDLcholesterol”.

[0004] Typical doses range from about 1 gram to about 3 grams daily.Nicotinic acid is normally administered two to four times per day aftermeals, depending upon the dosage form selected. Nicotinic acid iscurrently commercially available in two dosage forms. One dosage form isan immediate or rapid release tablet which should be administered threeor four times per day. Immediate release (“IR”) nicotinic acidformulations generally release nearly all of their nicotinic acid withinabout 30 to 60 minutes following ingestion, as illustrated in FIG. 1.The other dosage form is a sustained release form which is suitable foradministration two to four times per day. See, however, U.S. Pat. No.5,126,145 issued to O'Neill. In contrast to IR formulations, sustainedrelease (“SR”) nicotinic acid formulations are designed to releasesignificant quantities of drug for absorption into the blood stream overspecific timed intervals, also as shown in FIG. 1. If the release occursat appropriate times, therapeutic levels will be maintained by SRnicotinic acid formulations over an extended period such as 12 or 24hours after ingestion.

[0005] The dosing regimen of IR nicotinic acid is known to provide avery beneficial effect on blood lipids as discussed in Knopp et al.;“Contrasting Effects of Unmodified and Time-Release Forms of Niacin onLipoproteins in Hyperlipidemic Subjects: Clues to Mechanism of Action ofNiacin”; Metabolism 34/7, 1985, page 647. The chief advantage of thisprofile is the ability of IR nicotinic acid to decrease totalcholesterol, LDL cholesterol, triglycerides and Lp(a) while increasingHDL particles. In fact, IR nicotinic acid has been well regarded as aneffective drug in the treatment of high cholesterol since about theearly 1960s. Unfortunately, IR nicotinic acid has never really becomewidely used because of the high incidence of flush that often occurswhen an IR dose is taken. That means an individual may develop avisible, uncomfortable, hot or flushed feeling three or four times a dayfor about one hour following each IR dose.

[0006] In order to avoid or reduce the cutaneous flushing, a number ofmaterials have been suggested for administration with an effectiveantihyperlipidemic amount of immediate release nicotinic acid, includingguar gum in U.S. Pat. No. 4,956,252, and mineral salts as disclosed inU.S. Pat. No. 5,023,245; or inorganic magnesium salts as reported inU.S. Pat. No. 4,911,917. These materials have been reported to avoid orreduce the cutaneous flushing side effect commonly associated withnicotinic acid treatment.

[0007] Another method of avoiding or reducing the side effectsassociated with immediate release nicotinic acid is the use of SRnicotinic acid formulations. SR nicotinic acid formulations are designedto slowly release the compound from the tablet or capsule. The slow drugrelease reduces and prolongs blood levels of drug in an attempt to lowerpeak nicotinic acid concentrations with the goal of reducing oreliminating nicotinic acid induced flush. Examples of currently marketedSR formulations of nicotinic acid include Nicobid® capsules(Rhone-Poulenc Rorer), Enduracin® (Innovative Corporation) andSloNiacin® (Upsher-Smith Laboratories, Inc., U.S. Pat. No. 5,126,145,which describes a sustained release niacin formulation containing twodifferent types of hydroxypropyl methylcellulose and a hydrophobiccomponent).

[0008] Studies in hyperlipidemic patients have been conducted with anumber of SR nicotinic acid products. These studies have demonstratedthat the sustained release products do not have the same advantageouslipid altering effects as IR nicotinic acid, and in fact often have aworse side effect profile compared to the IR products. The majordisadvantage of the SR formulations, as can be seen in Knopp et al., in1985, is the significantly lower reduction in triglycerides (−2% for thesustained release versus −38% for the immediate release) and lowerincrease in HDL cholesterol, represented as HDL₂ particles which areknown by the art to be most beneficial, (−5% for the sustained releaseversus +37% for the immediate release).

[0009] Additionally, SR nicotinic acid formulations have been noted ascausing greater incidences of liver toxicity as described in Henken etal.: Am J Med, 91:1991 (1991) and Dalton et al.: Am J Med, 93:102(1992). There is also great concern regarding the potential of theseformulations in disrupting glucose metabolism and uric acid levels.

[0010] In a recent edition of the Journal of the American MedicalAssociation, an article appeared which presented research resultsinvestigating the liver toxicity problems associated with an SR form ofnicotinic acid. See McKenney et al.: A Comparison of the Efficacy andToxic Effects of Sustained- vs. Immediate-Release Niacin inHypercholesterolemic Patients, JAMA, (271)9: 672 (Mar. 2, 1994). ThisMcKenney et al. article presented a study of twenty-three patients. Ofthat number, 18 or 78 percent were forced to withdraw because liverfunction tests (LFTs) increased indicating potential liver damage. Theconclusion of the authors of that article was that the SR form ofnicotinic acid “should be restricted from use.”

[0011] A similar conclusion was reached in an article authored byrepresentatives of the Food and Drug Administration. See Radar, et al.:Hepatic Toxicity of Unmodified and Time-Release Preparations of Niacin,JAMA, 92:77 (January 1992). Because of these studies and similarconclusions drawn by other health care professionals, the sustainedrelease forms of nicotinic acid have experienced limited utilization.

[0012] Consistent with these conclusions, certain IR formulations areFDA approved for the treatment of hyperlipidemia. The SR products,however, are not FDA approved for the treatment of hyperlipidemia andmay only be marketed as over-the-counter nutritional supplies. Asover-the-counter nutritional supplements, SR nicotinic acid formulationsare not subject to the rigorous FDA imposed in vivo and in vitro testingrequired of prescription SR products. Rather, anyone can market an SRnicotinic acid product as a nutritional supplement as long as it ismanufactured using “Good Manufacturing Procedures.” Notwithstandingtheir commercial availability in the United States, many investigatorshave recommended that the SR nicotinic acid products be removed fromnon-prescription status because of their incidence of hepatotoxicity andthe lack of sufficient medical testing to support their marketing. SeeDalton, T. A. et al.: Am J Med, (93): 102-104 (1992); Etchason, J. A. etal.: Mayo Clin Proc, (66): 23-28 (1991); and Fischer, D. J. et al.:Western J. Med., (155)4:410-412 (1991).

[0013] In designing an SR nicotinic acid product, the pharmacokineticscan have a considerable impact on whether a particular SR nicotinic acidwill produce satisfactory results after in vivo administration. Orallyadministered drugs, such as nicotinic acid, are absorbed and enter thecapillaries and veins of the upper GI tract and are transported by theportal vein directly to the liver before entering the generalcirculation of the body. The entire absorbed drug is exposed to theliver during its first pass through the body. If a drug is subject to ahigh hepatic clearance, i.e., it is rapidly metabolized by the liver,then a substantial fraction of the absorbed dose is extracted from theblood and metabolized before it reaches the systemic circulation. Thisphenomenon is characterized as the “first pass effect.” The consequenceof this phenomenon is a significant reduction in bioavailability. Insome instances, the first pass effect is so large as to render oraladministration of a drug ineffective.

[0014] The pharmacokinetics of nicotinic acid have been some whatstudied in the past. Nicotinic acid is well absorbed from thegastrointestinal tract and is subjected to an extensive first passeffect. More particularly, nicotinic acid is metabolized into many byproducts as depicted in FIG. 2 and undergoes saturable first passmetabolism resulting into two metabolic pathways. Pathway 2 is thesaturable pathway, whereas Pathway 1 is the secondary metabolic processthat is initiated only after all of the enzymes in Pathway 2 areoccupied or “saturated.” In other words, as the concentration ofnicotinic acid accumulates or backs up due to the “saturation” of theenzymes in Pathway 2, the secondary metabolic process, i.e., Pathway 1,is initiated. The nicotinic acid metabolites produced in both pathwaysare common to all nicotinic acid formulations either IR or SR. As shownin FIG. 2, Pathway 1 includes nicotinic acid and nicotinuric acid(“NUA”), and Pathway 2 includes the phase I metabolites, nicotinamide(“NAM”), 6-hydroxy nicotinamide (“6HN”), nicotinamide-N-oxide (“MNO”),N-methyl-nicotinamide (“MNA”) and nicotinamide adenine dinucleotide(“NAD”). As further shown in FIG. 2, Pathway 2 includes the metabolitesof MNA, N-methyl-2-pyridone-5-carboxamide (2PY) andN-methyl4pyridone-5-carboxamide (4PY), and the entire NAD cycle which isnecessary in nearly all biochemical processes within the cells.

[0015] Compounds such as nicotinic acid which are subject to a firstpass metabolism are considered to have non-linear pharmacokinetics. Anincrease or decrease in the dose administered will not necessarilyproduce the corresponding increase or decrease in observed blood levels.This is believed to be dependent upon whether the metabolic level of theliver has been exceeded. Therefore, it is thought that the percent ofadministered nicotinic acid dose metabolized before the compound leavesthe liver is dependent upon the dose administered and the release rate.

[0016] It has been long appreciated by those of skill in the art that itcan be difficult to design SR formulations for compounds, like nicotinicacid, that are subjected to the first pass effect. See Urquhart et al.:Controlled-Release Pharmaceuticals, Am Pharm Assoc, (1979). Whereas anIR product allows saturation of the enzymes and a significant increasein blood levels, an SR product releasing similar quantities of drug at aslow rate will typically either not produce saturation of the primarymetabolic pathway or only initiate the secondary metabolic process to aminimal extent. Consequently, a larger percentage of an SR dose will bemetabolized before it has had an opportunity to clear the liver.Moreover, the particular time at which a drug should be released variessignificantly with each drug and is dependent upon its pharmacokinetics.The difficulty of correctly predicting an appropriate release pattern iswell known to those skilled in this art.

[0017] Therefore, it would be a valuable contribution to the art todevelop an extended release nicotinic acid formulation for once a daynocturnal administration for approval by the FDA which would providehyperlipidemic individuals with “balanced lipid alteration,” i.e.,reductions in total cholesterol, LDL cholesterol, triglycerides andLp(a) as well as increases in HDL particles, with an acceptable safetyprofile, especially as regards to liver toxicity and effects on glucosemetabolism and uric acid levels.

SUMMARY OF THE INVENTION

[0018] In brief, the present invention alleviates and overcomes certainof the above-identified problems and shortcomings of the present stateof nicotinic acid therapy through the discovery of novel nicotinic acidformulations and methods of treatment.

[0019] Generally speaking, novel nicotinic acid formulations have beendiscovered that optimize blood levels of nicotinic acid over a period ofabout 5 to about 9 hours when administered as a single oral dose forachieving a balanced lipid alteration in individuals at a time when therate of serum lipids, lipoproteins, cholesterol and cholesterolprecursor biosynthesis is believed to be at its highest. In other words,the novel nicotinic acid formulations have been uniquely formulated foradministration as a single dose, preferably during the evening or atnight when the nicotinic acid levels subsequently achieved are effectivefor substantially lowering the levels of total cholesterol, LDLcholesterol, triglycerides and/or Lp(a) as well as raising the levels ofIDL particles, all of which are primarily nocturnally synthesized.Preferably, the nicotinic acid formulations are administered at or afteran evening meal or low fat snack but before bedtime, i.e., between about6 pm and 12 am, preferably between about 8 pm and 12 am, and mostpreferably between about 8 pm and 10 pm.

[0020] The amount of nicotinic acid that is administered is effective tosubstantially lower at least one serum lipid, such as total cholesterol,LDL cholesterol, triglycerides, and/or Lp(a) and elevated HDL-C, withoutcausing drug-induced hepatotoxicity to levels which would require thetherapy to be discontinued. In other words, a single 1 to 3 gram dose ofa nicotinic acid formulation of the present invention administeredbetween about 6 pm and 12 am is believed to be as effective as an equalor higher daily dosage of nicotinic acid administered in two to fourdivided doses between, e.g., 8 am and 8 pm.

[0021] Furthermore, because at least the majority of the nicotinic acidis released and metabolized in vivo during a limited predeterminedperiod of time of about 5 to about 9 hours, the liver is not beingexposed to constant levels of nicotinic acid which results during theadministration of long-term, spaced daily doses of SR nicotinic acid.Thus, it is believed that the nicotinic acid formulations of the presentinvention are unlikely to cause individuals to develop dose-limitinghepatotoxicity when used as a single daily dose administered in atherapeutic amount.

[0022] The nicotinic acid formulations in accordance with the presentinvention have been uniquely designed as intermediate releaseformulations which can be characterized by one or more of the followingbiopharmaceutic characteristics: (1) an in vivo stair-stepped orsigmoidal-shaped absorption profile when the plasma nicotinic acid orNUA data is deconvoluted using the Wagner-Nelson method; (2) an in vitrodissolution profile; (3) a fit factor F₂; (4) urine metabolite recovery;(5) AUC; (6) Cmax; and/or (7) Tmax. By the term “intermediate release,”it is used herein to characterize the nicotinic acid formulations of thepresent invention which release their medication in vitro or in vivoover a period of time which is greater than about 1 to 2 hours, i.e.,slower that IR niacin, but less than about 10 to 24 hours, i.e., fasterthan SR niacin.

[0023] It is therefore, an object of the present invention to provide acomposition of nicotinic acid or any compound which is metabolized bythe body to form nicotinic acid for treating hyperlipidemia.

[0024] It is another object of the present invention to provide acomposition as above, which as a time release sustaining characteristic.

[0025] It is yet another object of the present invention to provide amethod for employing a composition as above, for treatinghyperlipidemia, which results in little or no liver damage.

[0026] At least one or more of the foregoing objects, together with theadvantages thereof over the known art relating to the treatment ofhyperlipidemia, which shall become apparent from the specification whichfollows, are accomplished by the invention as hereinafter described andclaimed.

[0027] In general, the present invention provides an improvedantihyperlipidemia composition of the oral type employing an effectiveantihyperlipidemic amount of nicotinic acid, wherein the improvementcomprises compounding the nicotinic acid with from about 5% to about 50%parts by weight of hydroxypropyl methylcellulose per hundred parts byweight of table or formulation.

[0028] The present invention also provides an orally administeredantihyperlipidemia composition which comprises from about 30% to about90% parts by weight of nicotinic acid; and, from about 5% to about 50%parts by weight of hydroxypropyl methylcellulose.

[0029] Generally speaking, the nicotinic acid formulations of thepresent invention are manufactured by first wet mixing (granulation)niacin and hydroxypropyl methylcellulose, the immediate-releaseexcipient, in a high-energy, high-shear mixer to produce dense niacinpellets. The pellets are then mixed with more hydroxypropylmethylcellulose and compressed into tablets. The resulting tablets arethen formed by a mixture of hydroxypropyl methylcellulose-niacingranulation and additional hydroxypropyl methylcellulose.

[0030] The present invention also includes a method of treatinghyperlipidemia in a hyperlipidemic. The method comprises the steps offorming a composition which comprises an effective antihyperlipidemicamount of nicotinic acid and an amount of excipients to provideintermediate release of drug. The method also includes the step oforally administering the composition to the hyperlipidemic nocturnally.

[0031] A method of treating hyperlipidemia in a hyperlipidemic accordingto the invention, comprises dosing the hyperlipidemic with an effectiveantihyperlipidemic amount of nicotinic acid or compound metabolized tonicotinic acid by the body. The dose is given once per day in theevening or at night, combined with a pharmaceutically acceptable carrierto produce a significant reduction in total and LDL cholesterol as wellas significant reduction in triglycerides and Lp(a), with a significantincrease in HDL cholesterol.

[0032] Once the niacin formulations of the present invention areswallowed or consumed, the tablets become wet and the hydroxypropylmethylcellulose surrounding the tablets is believed to form thin gellayers. Any granular nicotinic acid exposed to the exteriors of thetablets will dissolve out of the tablets resulting in an intermediaterate of nicotinic acid for absorption. As the nicotinic acid leaves theouter surfaces of the tablets, gastrointestinal fluid can reach deeperinto the tablets resulting in thicker gel layers and the dissolution ofthe intermediate release nicotinic acid granules surrounded by the gellayers. The gel layers then act as controlled release layers fordissolved nicotinic acid originating in the intermediate releasenicotinic acid granules.

[0033] The above features and advantages of the present invention willbe better understood with reference to the following FIGS. , detaileddescription and examples. It should also be understood that theparticular methods and formulations illustrating the present inventionare exemplary only and not to be regarded as limitations of the presentinvention.

DESCRIPTION OF THE FIGS.

[0034] With reference to the accompanying Figs., which are illustrativeof certain embodiments within the scope of this invention:

[0035]FIG. 1 is a graph depicting the typical in vitro dissolutionprofiles of an immediate release niacin formulation and a sustainedrelease niacin formulation;

[0036]FIG. 2 is a schematic depicting the metabolic pathways of niacinin the liver and the niacin metabolites that are common to all niacinformulations, including the immediate and sustained releaseformulations. Pathway 1 includes niacin and nicotinuric acid (NUA) andPathway 2 includes the Phase I metabolites, nicotinamide (“NAM”),6-hydroxy nicotinamide (“6HN”), nicotinamide-N-oxide (“MNO”),N-methyl-nicotinamide (“MNA”) and nicotinamide adenine dinucleotide(“NAD”). FIG. 2 also depicts that Pathway 2 includes the metabolites ofMNA, N-methyl-2-pyridone-5-carboxamide (2PY) andN-methyl-4-pyridone-5-carboxamide (4PY), and the entire NAD cycle whichis necessary in nearly all biochemical processes within the cells;

[0037]FIG. 3 is a graph depicting an in vivo stair-stepped orsigmoidally-shaped absorption profile or curve which has beendeconvoluted using the Wagner-Nelson method from the mean of plasmacurves for niacin released from Niaspan® formulations of the instantinvention. The profile shows that niacin is absorbed at a lesser rateduring about the first two hours and at a significantly faster ratebetween about hours 2 and 7 following ingestion. The profile also showsthat approximately 100% of the absorbable niacin is absorbed at about7.3 hours after ingestion;

[0038]FIG. 4 is a graph depicting individual in vitro dissolutionprofiles of a Niaspan® formulation and thirteen (13) commerciallyavailable sustained release niacin formulations; and

[0039]FIG. 5 is a chart depicting the percent of a niacin dose recoveredin urine as metabolites following consumption of a dose of 500 mg ofNicolar®, an immediate release niacin product, doses of 2000 mg, 1500 mgand 1000 mg of Niaspan®, and a dose of 2000 mg of Goldline's timereleased niacin, a sustained release product. The Phase I pathwayconcerns those metabolites that are generated by the oxidative pathway.The Phase II pathway includes niacin and nicotinuric acid (NUA)metabolites. The chart shows that a 1500 mg dose of Niaspan® producesless Phase II pathway metabolites than a 1500 mg dose of an immediaterelease niacin formulation, i.e., Nicolar®. The chart also shows that a2000 mg dose of Niaspan® produces less Phase I pathway oxidativemetabolites than a similar dose of a sustained release niacin product,i.e., Goldline's timed release niacin.

DETAILED DESCRIPTION OF THE INVENTION

[0040] By way of illustrating and providing a more complete appreciationof the present invention and many of the attendant advantages thereof,the following detailed description and examples are given concerning thenovel methods and formulations.

[0041] Turning now to the biopharmaceutic characteristics of the novelnicotinic acid formulations, the nicotinic acid formulations of thepresent invention exhibit an in vivo stair-stepped or sigmoidal-shapedprofile when the plasma curves for nicotinic acid or NUA aredeconvoluted using the Wagner-Nelson method, as taught in Wagner, J. G.et al.: J Pharm Sciences, 52:610-611 (1963), which is incorporatedherein by reference in its entirety. As illustrated in FIG. 3, thestair-stepped or sigmoidal-shaped time plot for nicotinic acid absorbedfrom the formulations of the instant invention is characterized by threephases, designated as phases A, B and C, and by the fact thatsignificant quantities of nicotinic acid are absorbed from suchformulations during phases A and B, and predominantly during phase B.Phase A constitutes the initial time period where minimal absorption ofnicotinic acid occurs, whereas phase B represents the period time thatfollows phase A where most of the absorption of nicotinic acid occurs.Phase C concerns that period of time when absorption of nicotinic acidgenerally ends.

[0042] In accordance with the present invention, phase A generallyoccurs at from about 1 to about 4 hours with a mean of about 2.3 hoursafter ingestion, and phase B generally occurs for about 4 to about 8hours with a mean of about 5 hours after phase A. Phase C generallyoccurs at about 5 to about 9 hours with a mean of about 7.3 hours afteringestion. See Tables 1 and 2. Also reported in Table 1, up to about 19%and preferably about 6.4% is absorbed during phase A, between about 78%and 100% and preferably about 90% is absorbed during phase B, with theremainder, if any, being absorbed during phase C.

[0043] As indicated above, deconvolution is calculated using theWagner-Nelson method of plasma niacin or NUA data generated fromfrequent blood sampling following the administration of the formulationsof the present invention to healthy human volunteers resulting in apercent absorbed time plot which is described in three phases:

[0044] Phase A—the initial time period where minimal absorption occurs;

[0045] Phase B—the subsequent time period where most of the absorptionoccurs; and

[0046] Phase C—the time when absorption has ended.

[0047] The expected values describing each Phase are recited in Table 1:TABLE 1 % Dose % Dose Absorbed Start Start range Absorbed/ AbsorptionEnd End range % Done Range (hrs) (hrs) hr rate range (hrs) (hrs)Absorbed (% hr) Phase A 0   NA 3.3  0-9.2 2.3 1.1-4.1  6.4   0-1.91Phase B 2.3 1.1-4.1 19.0 14.1-26.1 7.3 5.1-9.1 90.7 78.4-100.4 Phase C7.3 5.1-9.1 0 0 NA NA 97.1 85.7-103.7

[0048] Table 2 represents the absorption rate parameters of nicotinicacid in 12 individuals who each ingested two, 1000 mg tablets ofNiaspan®, and the minimum, maximum, mean and median for each of those 12individuals tested. Table 1 is a summary of the results in Table 2.TABLE 2 First End Second End Absorption First Absorption Second Rate (%Absorption Rate (% Absorption Subject Dose/Hr) Phase (hr) Dose/Hr) Phase(hr) 1 1.90 4.08 21.82 8.08 2 4.07 2.08 15.86 8.08 3 5.55 2.08 20.946.08 4 4.39 1.08 15.57 7.08 5 9.16 2.08 26.12 5.08 6 4.07 1.08 23.225.08 7 0.00 3.08 14.28 9.08 8 3.24 2.08 18.08 7.08 9 0.00 2.08 25.106.08 10  0.00 2.08 16.21 8.08 11  6.96 2.08 14.09 8.08 12  0.00 3.0816.54 9.08 Mean 3.28 2.25 18.99 7.25 Minimum 0.00 1.08 14.09 5.08Maximum 9.16 4.08 26.12 9.08 Median 3.65 2.08 17.31 7.58

[0049] The unique nicotinic acid formulations of the present inventiontherefore result in subsequently all of the nicotinic acid beingabsorbed within about 5 to about 9 hours, preferably between about 6 andabout 8 hours and most preferably between about 7 and 8 hours, followingingestion. Minimal nicotinic acid is absorbed thereafter. It is believedthat Phase A results in the plasma concentration of nicotinic acid orNUA prior to the saturation of Pathway 2, whereas phase B concerns theplasma concentration of nicotinic acid or NUA after Pathway 2 has beensaturated. It is further believed that the stair-stepped orsigmoidal-shape developed for NUA are as reliable as that developed fornicotinic acid, since the Tmax and shape of the plasma curve parallelsthe Tmax and shape of the plasma curve for nicotinic acid. The initialabsorption of nicotinic acid allows for the initial obtainment oftherapeutic levels of nicotinic acid and the second absorption period,phase B, optimizes therapeutic levels thereafter.

[0050] Each nicotinic acid formulation of the instant invention willtypically exhibit the following dissolution profile in U.S.P. XXII,Apparatus I, 900 ml of deionized water at 37° C., baskets at 100 RPM, asindicated in Table 3. TABLE 3 Dissolution range Dissolution range forFDA approved Niaspan ® for all Niaspan ® Niaspan ® tablet TimeSpecification strengths tested in batches for all (hours) PercentDissolved humans strengths 0 0 0 0 1 less than 15  9.6-13.8  9.8-12.3 315-30 21.2-27.8 20.9-26.7 6 30-45 35.1-44.2 35.3-44.1 9 40-60 45.6-58.544.8-58.7 12  50-75 56.2-72.0 59.5-70.7 20  greater than 75  78.1-103.9 84.4-120.5

[0051] By the term “dissolution,” it is used herein to refer to thatpercent of a drug, e.g., nicotinic acid, which is dissolved or releasedin vitro from a formulation into a dissolution medium over a selectedperiod of time under certain conditions. With respect to the shape ofthe dissolution curve concerning the specifications in Table 3 relativeto a target dissolution curve for each Niaspan® tablet strength, thetarget dissolution curve for each of the Niaspan® tablet strengths areas follows: TABLE 4 Time 250 and 325 mg 500 mg 750 mg 1000 mg (hours) (%released) (% released) (% released) (% released) 0 0  0  0  0  1 11.310.6 10.3 11.8 3 24.1 22.9 22.0 25.5 6 40.2 38.0  36.60 41.3 9 54.2 51.449.4 54.8 12  67.0 63.4 61.6 66.3 20  91.7 88.4 87.2 98.4

[0052] It is believed that the nicotinic acid formulations of thepresent invention are responsible for a controlled absorption profilethat is intermediate to that of IR and SR nicotinic acid formulationscurrently commercially available. As depicted in FIG. 4 and Tables 3, 4,5A and 5B, and especially Tables 5A and 5B, the dissolution profile ofthe nicotinic acid formulations of the present invention, i.e.,Niaspan®, is slower than that of IR niacin, but different than that ofSR niacin commercially available products. The uniqueness of thedissolution profile for the nicotinic acid formulations of the presentinventions is shown in FIG. 4 and Tables 3,4, 5A and 5B.

[0053] Tables 5A and 5B depict dissolution data for two representativelots of Niaspan® 500 mg tablet strength and other commercially availableSR nicotinic acid 500 mg products. The dissolution data of Table 5represents two lots of Niaspan® 500 mg tablets which fall within therange of the dissolution profile provided for Niaspan® tablets of thepresent invention. Also as illustrated in FIG. 4 and Tables 3, 4 and 5Aand 5B, and in particular Tables 5A and 5B, when the dissolutionprofiles of sixteen (16) over-the-counter SR niacin products arecompared to that of Niaspan®, none of the dissolution curves for thoseproducts are equivalent to that of Niaspan®.

TABLES 5A and 5B Brand Comparison

[0054] TABLE 5A Goldline Goldline Goldline Niaspan ® Niaspan ®Goldline86 Nicobid 12 87 89 Rugby MO Rugby SL Time Cap Time 500 mgK4061A-1 Low High 86A6014C MN0928 12L51229 87L51081 89G5612C M070E5L01707 A051 hrs 500 mg 500 mg Limit Limit 250 mg 500 mg 500 mg 500 mg500 mg 500 mg 500 mg 500 mg 0 0  0  — — 0  0  0  0  0  0  0  0  1 10.310.8 15  5.4  4.9 12.6 10.8 16.5 16.7 11.7 14.9 3 22.5 23.9 15 30 16.914.4 28.0 26.5 39.0 40.6 27.1 32.4 6 37.6 39.0 30 45 32.9 26.9 47.8 43.957.3 62.9 46.1 50.6 9 51.2 51.8 45 60 42.9 37.0 58.8 58.0 67.3 73.0 60.462.9 12  62.8 63.1 50 75 56.0 43.9 65.7 69.4 73.0 81.7 72.2 70.3 20 87.1 85.2 75 72.8 58.3 77.0 91.7 81.6 89.3 94.3 81.3

[0055] TABLE 5B Niaspan ® Majopr Upsher-S Geneva Mason Endurance RugbyNicobid Goldline Time Niaspan ® K4061A-1 Low High 5F00753 16020 4B124501199 11504 K053G MN1937 89A51566 hrs 500 mg 500 mg Limit Limit 500 mg500 mg 500 mg 500 mg 500 mg 500 mg 500 mg 500 mg 0 0 0 — — 0 0 0 0 0 0 00 1 10.3 10.8 15 16.6 13.7 20.7 11.3 11.0 31.9 10.8 11.0 3 22.5 23.9 1530 38.7 28.1 43.2 27.1 24.2 42.2 27.2 30.6 6 37.6 39.0 30 45 53.7 45.760.0 45.4 36.5 61.0 38.1 53.2 9 51.2 51.8 45 60 61.7 61.4 71.5 60.4 48.172.9 51.5 12 62.8 63.1 50 75 70.6 73.5 77.8 71.0 56.4 77.9 61.1 74.7 2087.1 85.2 75 78.3 92.8 87.6 90.5 71.9 84.0 75.9 85.6

[0056] Similarity between the test and the target dissolution curveswithin a tablet strength can be determined through the calculation ofthe fit factor F₂. See Moore J W, Flanner H H.: Mathematical comparisonof dissolution profiles, Pharmaceutical Technology, 64-74 (June 1996),which is incorporated herein by reference in its entirety. In otherwords, the fit factor F₂ is calculated using the difference between thepercent dissolved at each time point for each dissolution profile. Ifthere is no difference between the percent dissolved at each time point,the fit factor F₂ equals 100. As the difference in percent dissolvedincreases, however, the fit factor F₂ value decreases. The fit factor F₂is determined by the following equation:$F_{2} = {50\quad \log \quad \left\{ {\left\lbrack {1 + {{1/n}{\sum\limits_{t = 1}^{n}{w_{t}\left( {R_{t} - T_{t}} \right)}^{2}}}} \right\rbrack^{- 0.5} \times 100} \right\}}$

[0057] where R_(t) is the dissolution value for the target profile at atime point t, T_(t) is the dissolution value for the test profile at thesame time point t, n is the number of time points on the dissolutionprofile and w_(t) is an optional weight factor. This equation is alogarithmic transformation of the sum of the mean square error betweenthe test and target profile, resulting in a number between 0 and 100.The fit factor F₂ is 100 when two dissolution profiles are identical anddecreases as the two profiles become more dissilimar. In other words,the smaller the fit factor F₂, the farther apart the products are fromone another. The fit factor F₂ will be positive as long as the averagedifference between the two curves is 100 or less.

[0058] The following Table 6 depicts the recommended fit factor F₂values for each of the Niaspan® tablet strengths. The recommended valuesare based on the range of fit factors F₂ between lots used in the NewDrug Application (NDA), made more specific by the determination ofbioequivalence to a target lot of Niaspan® tablets. TABLE 6 250 and 500mg 750 mg 1000 mg Criteria derived 325 mg tablet tablet tablet tabletfrom: strengths strength strength strength Bioequivalence ≧79.0 ≧79.0≧79.0 ≧44.0 Studies

[0059] The term “bioequivalence,” as used herein, means the absence of asignificant difference in the rate and extent to which the activeingredient or active moiety in pharmaceutical equivalents orpharmaceutical alternatives becomes available at the site of drug actionwhen administered at the same molar dose under similar conditions in anappropriately designed study. See Code of Federal Regulations, Title 21,Apr. 1, 1997 edition, Part 320.1, Definitions (e) Bioequivalence, page195, which is incorporated by reference herein in its entirety.

[0060] Table 7 also depicts the fit factor F₂ for thirteen (13) of thesixteen (16) over-the-counter SR niacin products referenced in Tables 5Aand 5B compared to the dissolution curve of Niaspan®. As can be seenfrom the fit factor F₂ data in Table 7, the thirteen (13)over-the-counter SR niacin products are not bioequivalent to Niaspan®,in view of the fact that the fit factor F₂ is less than 79 for all suchproducts. TABLE 7 Niaspan ® GTRN 250 Nicobid Goldline 12 Goldline 87Goldline 89 Rugby MO K4061A-1 86A6014C MN0928 12L51229 87L51081 89G5612CM070E Brand 500 mg 250 mg 500 mg 500 mg 500 mg 500 mg 500 mg F2 79 54.339.4 60.6 64.5 45.0 59.6 Rugby 5L Time Cap Major Upsher-Smith GenevaMason Endurance 5L01707 A051G SF00753 16020 4B124 501199 11504 Brand 500mg 500 mg 500 mg 500 mg 500 mg 500 mg 500 mg F2 38.7 57.3 53.9 48.7 56.339.3 60.8 59.6

[0061] The percent of the dose excreted in urine as niacin and NUA aswell as the percent of the dose excreted in urine as metabolites otherthan niacin and NUA relative to the total dose recovered is due tosaturable first-pass metabolism. Thus, because it is now discovered thatthe rate of niacin absorption determines the amount of drug that isexcreted as niacin and NUA versus all other niacin metabolites, the rateof absorption can be used to control the amount of Pathway 1 and Pathway2 metabolites produced. This can be depicted from urine collection dataobtained following multiple-daily administrations of Niaspan® to healthyhuman volunteers, as illustrated in Table 8. TABLE 8 2 × 500 mg 2 × 750mg 2 × 1000 mg 3 × 1000 mg Metabolites Niaspan ® Niaspan ® Niaspan ®Niaspan ® recovered tablets tablets tablets tablets Niacin + NUA Mean12.2% 21.3% 32.4% 41.9% Range 4.5-25.7% 11.0-44.8% 21.7-48.2% 25.4-66.1%All others Mean 87.8% 78.7% 67.6% 58.1% Range 74.3-95.5% 55.2-89.0%51.8-78.3% 33.9-74.6%

[0062] Table 8 reflects the range and mean of metabolites recovered inthe urine from 27 individuals at 24 hours after administration of therespective Niaspan® tablet strengths once per day at night for 6 days.The numbers recited in Table 8 represent the mean and range for all 27patients for each dosage regimen.

[0063] Turning now to FIG. 5, it depicts actual metabolite recovery datafrom two studies involving six subjects where the amount of Phase Ipathway (Pathway 2) and Phase II pathway (Pathway 1) metabolitesexcreted in urine at steady-state following the administration of IR(500 mg tid) and SR niacin (500 mg qid), which were quantified. FIG. 5further depicts that SR niacin results in little Phase II pathway(Pathway 1) metabolites (niacin and nicotinuric acid) and that almostall of the niacin from the SR formulation was converted to Phase Ipathway (Pathway 2) oxidative metabolites. Moreover, little to no flushwas reported by the individuals who received the SR niacin product inthis study, while nearly all subjects who received IR niacin experiencedflush. Because all six subjects in this study who consumed the SR niacinproduct experienced elevations in liver enzymes at least 3 times greaterthan the upper limit of normal, the study was prematurely terminated. Inthe IR niacin study where much less Pathway 2 metabolites were produced,no subjects experienced elevations in liver enzymes. It is believedthat, because the SR niacin products are designed with a slowdissolution or absorption rate which results in a situation where therate of niacin presentation to the liver is so slow that Pathway 2 isnever saturated and the major metabolites produced are Pathway 2metabolites, hepatotoxicity will ensue from SR niacin products. On theother hand, when IR niacin is administered, it is believed that, becausethe presentation of niacin to the liver is so rapid that Pathway 2 issaturated almost immediately, the major metabolites produced are Pathway1 metabolites and the patient experiences flush.

[0064] As compared to the IR and SR niacin formulations, the uniqueabsorption rate of Niaspan® is believed to result in a urine metaboliteprofile that balances the extremes of these two metabolic profiles. Inother words, the unique absorption profile following Niaspan®administration balances the Pathway 1 and Pathway 2 metabolites therebyminimizing the risk of drug-induced hepatotoxicity at the expense ofpossibly causing some flush. To minimize the flush, the unique titrationregimen recommended at the beginning of Niaspan® therapy is designed toallow the body to down regulate or desensitize itself from theprostaglandin effects (PGD₂) resulting from the administration ofniacin. For those individuals who are initiating niacin therapy, it ispossible to avoid significant flushing by starting with a uniqueNiaspan® titration pack. In accordance with the present invention, thenovel titration packs include Niaspan® tablets in at least the followingthree dosage regimens, i.e., 375 mg, 500 mg and 750 mg, and aregenerally administered as follows: the new patient receives Niaspan® 375mg Once-A-Night™ for seven days, followed by Niaspan® 500 mgOnce-A-Night™ for seven days, and then Niaspan® 750 mg Once-A-Night™ forseven days, after which they may start receiving therapeutic doses ofNiaspan® starting at 1000 mg Once-A-Night™ as two, 500 mg tablets.

[0065] Once titrated, it is important for the patients to taketherapeutic doses of Niaspan® as directed in the labeling to avoid therisk of significant flushing early in the initial therapy andhepatotoxicity later in the therapy. That is, patients should take two,500 mg Niaspan®) tablets for a 1000 mg dose, two, 750 mg Niaspan®tablets for a 1500 mg dose and two, 1000 mg Niaspan® tablets for a 2000mg dose. It is believed that early flushing and subsequenthepatotoxicity can be avoided by following such directions in view ofthe fact that the 375 mg and 500 mg Niaspan® tablets are notbioequivalent to the 750 mg and 1000 mg Niaspan® tablets, i.e., the 375mg, 500 mg and 750 mg Niaspan®O tablets release niacin at a slower ratethan the Niaspan® 1000 mg tablets. Moreover, the 375 mg and 500 mgNiaspan® tablets are believed to release niacin at the slowest rate.Thus, and in accordance with the present invention, early in niacintherapy, when a patient is most susceptible to flush and taking lowdoses, the patient should receive the slower dissolving Niaspan® tabletsto avoid quick saturation of Pathway 2 and to permit the body todesensitize itself from the prostaglandin effects (PDG₂) resulting fromelevated niacin concentrations, so that flush can be avoided. However,as the patient is titrated to higher doses ( no more than about S00 mgincrements at four-week intervals), the Niaspan® tablets used shouldrelease their niacin at faster rates to reduce the risk ofhepatotoxicity. It is believed that, at this point, the patientsprostaglandin system has acclimated itself to niacin and the risk offlush is minimized.

[0066] Other biopharmaceutic characteristics of the Niaspan® tabletsinclude AUC, Cmax and Tmax. By the term “AUC,” it refers to the areaunder a plasma concentration curve of niacin or NUA and is based uponthe rate and extent of absorption of niacin following ingestion of acertain dose of a niacin formulation. By the term “Cmax,” as usedherein, it is meant to refer to the peak or maximum concentration ofniacin or NUA achieved in the plasma following ingestion of a certaindose of a niacin formulation. Cmax occurs generally at about the timewhen the niacin in the formulation has been almost completely absorbedtherefrom, and it too is based upon the rate and extent of absorption ofniacin following ingestion of a certain dose of a niacin formulation.The term “Tmax” refers to the time that Cmax occurs following ingestion.The Tmax for the Niaspan® products of the present invention generallyoccurs between about 5.6 hours and about 6 hours following ingestion,which believed to be due in part to the saturable first pass effect ofthe liver.

[0067] Turning now to Table 9, it depicts both AUC and Cmax data forniacin and NUA obtained from the administration of a single dose ofNiaspan® at the dosage strengths identified therein to individuals fromwhom blood was withdrawn at frequent intervals over a 24 hour periodfollowing ingestion to detect the niacin and NUA concentrations fromwhich the absorption rate of niacin can be determined. According toTable 9, the 375 mg Niaspan® tablets have a niacin Cmax of about 3.39μg/ml and AUC of about 5.8 μghr/ml and an NUA Cmax of about 2.4 μg/mland an AUC of about 9.6 μghr/ml. Table 9 further reports that the 500 mgNiaspan® tablets have a niacin Cmax in the range of from about 1.13μg/ml to about 10.1 μg/ml with a mean of about 3.71 μg/ml and an AUC inthe range of about 1.8 μghr/ml to about 33.7 μghr/ml with a mean ofabout 8.9 μghr/ml. Still further, Table 9 reports that the 500 mgNiaspan® tablets have an NUA Cmax in the range of about 1.62 μg/ml toabout 3.4 μg/ml with a mean of about 2.18 μg/ml and an AUC in the rangeof about 5.5 μghr/ml to about 15.7 μghr/ml with a mean of about 8.7μghr/ml.

[0068] Table 9 further reports that the 750 mg Niaspan® tablets have aniacin Cmax in the range of from about 7.68 μg/ml to about 9.11 μg/mlwith a mean of about 8.40 μg/ml and an AUC in the range of about 21.1μghr/ml to about 21.5 μghr/ml with a mean of about 21.3 μghr/ml. Stillfurther, Table 9 reports that the 750 mg Niaspan® tablets have an NUACmax in the range of about 2.97 μg/ml to about 3.2 μg/ml with a mean ofabout 3.09 μg/ml and an AUC in the range of about 11.5 μghr/ml to about12.7 μghr/ml with a mean of about 12.1 μghr/ml.

[0069] Table 9 further reports that the 100 mg Niaspan® tablets have aniacin Cmax in the range of from about 9.29 μg/ml to about 16.6 μg/mlwith a mean of about 12.54 μg/ml and an AUC in the range of about 24.2μghr/ml to about 42.6 μghr/ml with a mean of about 33.2 μghr/ml. Stillfurther, Table 9 reports that the 1000 mg Niaspan® tablets have an NUACmax in the range of about 2.81 μg/ml to about 4.45 μg/ml with a mean ofabout 3.55 μg/ml and an AUC in the range of about 12.0 μghr/ml to about18.8 μghr/ml with a mean of about 15.4 μghr/ml. TABLE 9 Niacin DoseTablet Cmax AUC NUA AUC mg Study mg ug/ml ughr/mL Cmax ug/ml ughr/mL1500 A 375 3.39 5.8 2.4 9.6 1500 B 500 10.1 33.7 3.4 15.7 1500 C 5005.76 15.7 2.33 10.1 1500 C 500 5.98 15.8 2.33 10.2 1500 A 500 3.04 5.82.25 9 1500 D 500 2.89 4.76 2.16 7.6 1500 D 500 3.14 5.1 2.31 8.6 1500 D500 2.36 3.1 1.98 7.2 1500 E 500 1.81 3.1 1.89 7 1500 E 500 1.13 1.81.62 5.5 1500 E 500 1.69 2.2 1.8 6 2000 F 500 4.66 11.6 2.28 9.3 2000 G500 2.02 4.6 2.06 9.0 1500 H 750 9.11 21.5 3.2 11.5 1500 I 750 7.68 21.13.2 11.5 2000 G 1000 11.6 31.4 3.35 14.3 2000 G 1000 9.39 24.2 2.91 122000 J 1000 15.8 42.6 4.21 18.4 2000 J 1000 16.6 41.4 4.45 18.8 2000 K1000 9.29 26.2 2.81 13.3

[0070] Turning now to the Once-A-Night™ administration of Niaspan®, itis believed that a significant amount of lipid synthesis occurs atnight. Thus, it is believed that the administration of Niaspan® in theevening or at bedtime produces niacin concentrations in the body at theoptimal time necessary to interfere with the conversion of free fattyacids into LDL-cholesterol, thereby producing its beneficial effects.The Once-A-Night™ administration regimen is also believed to minimizethe risk of hepatotoxicity as follows. Because SR niacin is generallyadministered at least twice daily and Niaspan® is administeredonce-daily at night, the SR niacin products will result in a greateraccumulation of Pathway 2 metabolites because it is re-administeredbefore sufficient metabolite has left the body. As a consequence, thePathway 2 metabolites will pass over the toxic threshold causingdrug-induced hepatotoxicity. On the other hand, Niaspan® produces lessPathway 2 metabolite and is administered less frequently allowingsufficient time for clearance of metabolites keeping their accumulationbelow the toxic threshold. Thus, it is believed that the uniquecombination of the controlled niacin absorption rate of Niaspan®, theadherence to the Niaspan® titration schedule and/or the Once-A-Night™administration regimen are responsible for the efficacy of Niaspan® andthe minimized flush and hepatotoxicity associated with itsadministration. In other words, it is believed that Niaspan'® uniqueabsorption rate profile combined with its unique titration schedule andits unique Once-A-Night™ regimen are responsible for its lower incidenceof flush relative to IR niacin, its minimal risk of drug-inducedhepatotoxicity relative to SR niacin, and its efficacy inhyperlipidemia.

[0071] The present invention employs nicotinic acid or a compound otherthan nicotinic acid itself which the body metabolizes into nicotinicacid, thus producing the same effect as described herein. The othercompounds specifically include, but are not limited to the following:nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminumnicotinate, niceritrol and d, 1-alpha-tocopheryl nicotinate. Each suchcompound will be collectively referred to hereinbelow by “nicotinicacid.”

[0072] As stated hereinabove, nicotinic acid has been employed in thepast for the treatment of hyperlipidemia, which condition ischaracterized by the presence of excess fats such as cholesterol andtriglycerides, in the blood stream. According to the present invention,an intermediate release composition of nicotinic acid is prepared as anexample. As indicated herein, “intermediate release” is understood tomean a composition or formulation which, when orally administered to apatient to be treated, the active ingredient will be released forabsorption into the blood stream over a period of time which is slowerthan that of IR niacin formulations, but faster and different than SRniacin products. For example, it is preferred that in a dosage of about1000-3000 milligrams (herein “mg(s)”) of nicotinic acid, approximately100 percent of the nicotinic acid will be released to the blood streamin about 5 to about 9 hours.

[0073] The specific intermediate release composition according to thepresent invention employs an effective antihyperlipidemic amount ofnicotinic acid. By “effective anithyperlipidemic amount” it isunderstood to mean an amount which when orally administered to a patientto be treated, will have a beneficial effect upon the physiology of thepatient, to include at least some lowering of total cholesterol, LDLcholesterol, triglycerides and Lp(a) and at least some increase in HDLcholesterol in the patient's blood stream. An exemplary effectiveantihyperlipidemic amount of nicotinic acid would be from about 250 mgsto about 3000 mgs of nicotinic acid to be administered according to theinvention as will be more fully described hereinbelow. This amount willvery dependent upon a number of variables, including the psychologicalneeds of the patient to be treated.

[0074] Preferably, there is also included in the intermediate releasecomposition according to the present invention, a swelling agent whichis compounded with the nicotinic acid, such that when the composition isorally administered to the patient, the swelling agent will swell overtime in the patient's gastrointestinal tract, and release the activenicotinic acid, or a compound which produces nicotinic acid into thegastrointestinal system for absorption into the blood stream, over aperiod of time. As is known in the art, such swelling agents and amountsthereof, may be preselected in order to control the time release of theactive ingredient. Such swelling agents include, but are not limited to,polymers such as sodium carboxymethylcellulose and methylcellulose andwaxes such as bees wax and natural materials such as gums or gelatins ormixtures of any of the above. Because the amount of the swelling agentwill vary depending upon the nature of the agent, the time release needsof the patient and the like, it is preferred to employ amounts of theagent which will accomplish the objects of the invention.

[0075] An exemplary and preferred swelling agent is hydroxypropylmethylcellulose, in an amount ranging from about 5% to about 50% partsby weight per 100 parts by weight of tablet or formulation. Thepreferred example will ensure a sustained time release over a period ofapproximately 5-9 hours as demonstrated by in vitro dissolutiontechniques known to the art.

[0076] A binder may also be employed in the present compositions. Whileany known binding material is useful in the present invention, it ispreferred to employ a material such as one or more of a group ofpolymers having the repeating unit of 1-ethenyl-2-pyrrolidinone. Thesepolymers generally have molecular weights of between about 10,000 and700,000, and are also known as “povidone”.

[0077] Amounts of the binder material will of course, vary dependingupon the nature of the binder and the amount of other ingredients of thecompositions. An exemplary amount of povidone in the presentcompositions would be from about 1% to about 5% by weight of povidoneper 100 parts by weight of the total formulation.

[0078] Processing aids such as lubricants, including stearic acid, mayalso be employed, as is known in the art. An exemplary amount of stearicacid in the present compositions would be from about 0.5% to about 2.0%by weight per 100 parts by weight of table or formulation.

[0079] Examples of various embodiments of the present invention will nowbe further illustrated with reference to the following examples.

[0080] General Experimental

[0081] In order to demonstrate the effectiveness of the compositions andmethod of the present invention over known antihyperlipidemiacompositions and methods heretofore known in the art, a number ofsubstantially identical composition were prepared according to thedisclosure hereinabove. The composition ingredients and amounts arelisted in Table IA hereinbelow. TABLE IA Test Tablet CompositionIngredient 375 mg 500 mg 750 mg Nicotinic Acid 375.0 500.0 750.0Hydroxypropyl 188.7 203.0 204.7 methylcellulose Povidone 12.9 17.2 25.9Stearic Acid 5.8 7.3 9.9 TOTAL 582.4 mg 727.5 mg 990.5 mg

[0082] The ingredients were compounded together to form a tablet. Morespecifically, Niaspan® once-daily tablets in accordance with the presentinvention utilize a hydrophilic matrix controlled drug delivery system.This is a dynamic system composed of polymer wetting, polymer hydrationand polymer disintegration/dissolution. The mechanism by which drugrelease is controlled depends on, for example, initial polymer wetting,expansion of the gel layer, tablet erosion and niacin solubility. Afterinitial wetting, the hydrophilic polymer starts to partially hydrate,forming a gel layer. As water permeates into the tablet increasingthickness of the gel layer, drug diffuses out of the gel layer. As theouter layer of the tablet becomes fully hydrated it erodes. It isbelieved that this erosion results in additional drug release. Thecontrolled release from this matrix delivery system can be modifieddepending on the type of molecular weight of hydrophilic polymer used.

[0083] A Niaspan® formulation consists of Niacin, Methocel® E10MPremium, Povidone K90 and Hystrene 5016 (stearic acid). Methocel® E10MPremium is utilized as a controlled-release agent in the Niaspan®formulation. Methocel is a partly O-methylated andO-(2-hydroxypropylated) cellulose and is available in several gradeswhich vary in terms of viscosity and degree of substitution. Methocel ismanufactured by Dow Chemical.

[0084] Povidone K90 is employed as a granulating/binding agent in aNiaspan® formulation. Povidone is a synthetic polymer consisting oflinear 1-vinyl-2-pyrrolidone groups, the degree of polymerization ofwhich results in polymers of various molecular weights, or as indicatedabove. It is characterized by its viscosity in aqueous solution,relative to that of water, expressed as a K-value, ranging from 10-120.Povidone K90 has an approximate molecular weight of 1,000,000. Povidoneis a hygroscopic, water soluble material. Povidone K90 presents in aNiaspan® formulation is manufactured by ISP (International SpecialityProducts). Hystrene 5016 is utilized as an external lubricant in theNiaspan® formulation. Hystrene 5016 is a mixture of stearic acid andpalmitic acid. The content of stearic acid is not less than about 40.0%and the sum of the two acids is not less than about 90.0%. Hystrene 5016is manufactured by Witco. Refer to Table IB for Niaspan®O formulationdetails.

[0085] Qualitatively, the four tablet strength formulations areidentical. The major component of each formulation is a granulatedmixture of Niacin, Methocel E10M and Povidone K90. The granulationprocess improves compression properties. TABLE IB Niaspan ® TabletFormulations Niaspan ® Product 375 mg 500 mg 750 mg 1000 mg Formulation,% Tablet Tablets Tablets Tablets Tablets Niacin 64.4  70.5  77.4  83.1 Methocel E10M 7.4 8.1 8.9 9.5 Premium (Intragranular) Povidone K90 2.22.4 2.7 2.9 Methocel E10M Premium 25.0  18.0  10.0  3.5 (Extragranular)Hystrene 5016 (Stearic Acid) 1.0 1.0 1.0 1.0 Tablet weight, mg 582.5 709.5  968.6  1203.6  

[0086] Niaspan® formulations are presented in white caplet shapetablets. Caplet dimensions differ with respect to product strength. The375 mg and 500 mg Niaspan® tablets are compressed with tooling measuringapproximately 0.687″ in length×0.281″ by width. The length and width ofthe 750 mg and 1000 mg tooling measures approximately 0.750″×0.320″.Target tablet weight and hardness dictate thickness across the fourNiaspan® products. The production of the Niaspan® tablets will now bedescribed generally as set forth below. Niaspan ® Granulation ProcessFlow Chart Raw Materials Process Flow Equipment Niacin Granulate Highshear granulator (Littleford Povidone K90 FM130) Methocel E10M(Intragranular) Purified Water

Dry Fluid bed drier (Gladd fluid bed drier)

Parcel size reduction Mill (Kemutec Betagrind)

[0087] Niaspan® Granulation Process Description

[0088] Niaspan® granulation raw materials are dispensed and granulatedin a high shear granulator. The wet granules are sieved into a fluid beddrier and dried. When the drying process is complete, the granules aremilled. Milling ensures uniform particle size distribution throughoutthe Niaspan® granulation. Niaspan ® Tablet Process Flow Chart RawMaterials Process Flow Equipment Niaspan ® Tablet Blend Methocel BlendMilled Niaspan ® granules Blender E10M with (Patterson-Kelley(Extragranular) extragranular Methocel E10M and V-Blender) HystreneHystrene 5016 5016 (Stearic acid)

Niaspan ® Table Manufacture Compress Niaspan ® Tablet Blend Rotarytablet press

[0089] Niaspan® Tablet Process Description

[0090] A Niaspan® tablet blend is manufactured by blending the Niaspan®granulation, extragranular Methocel E10M and Hystrene 5016. Thequantities of each Niaspan® tablet blend component will depend on theparticular Niaspan® dose being manufactured (refer to Table IB). ANiaspan® tablet blend is compressed to form Niaspan® tablets. Niaspan®tablet physical properties will vary depending on the particularNiaspan® dose being manufactured.

[0091] Production of Niaspan® tablets will now be discussed in greaterdetail. The initial stage of manufacturing is the same for all fourtablet strengths of Niaspan® (375, 500, 750 and 1000 mg). One batch ofNiaspan® granulation is comprised of four individual 40.0 kg unites ofgranulation which are processed separately, but under like conditions.The four individual granulations are sampled and tested individually andsubsequently released for blending. The base granulation is not strengthspecific and may be used to manufacture any tablet strength of Niaspan®.

[0092] The ingredients in the base granulation are set froth in Table ICbelow: TABLE IC Quantity per % per Quantity kilogram kilogram pergranulation granulation 160.00 kg Component Function (kg) (%) batch (kg)Niacin, USP Drug Substance 0.87 87.00 139.20 Povidine, UPS Binder 0.033.00 4.80 Methocel USP, Controlled- 0.10 10.00 16.00 E10M Release AgentPremium CR Grade Purified Water, Granulation 0.00* 0.00 48.0 USP ReagentTotal 160.00

[0093] Raw materials are quantatively dispensed into appropriatelylabeled double polyethylene-lined containers using calibrated scales.Purified Water, USP is dispensed into an appropriate vessel from whichit is later pumped during the wet-massing operation.

[0094] A Littleford FM130 granulator is charged with approximately onehalf of the Niacin, USP required for the process unit (˜17.4 kg)followed by about 4.00 kg of Methocel, USP E10M Premium CR Grade; about1.20 kg of Povidine, USP; and the balance of the Niacin, SP (˜17.40 kg).The powder bed is dry mixed in the Littleford FM130 granulator, withchoppers on, for approximately 1 minute. At the completion of the1-minute pre-mix cycle, about 12.0±0.05 kg of Purified Water, USP aresprayed onto the powder bed at a rate of about 2.40±0.24 kg/minute.Immediately following the addition of the Purified Water, USP, the unitis granulated for about 5 minutes.

[0095] The granulated unit is discharged into double polyethylene-linedcontainers and then manually loaded into a Glatt bowl while being passedthrough a #4 mesh screen. The Glatt bowl is loaded into a Glatt TFO-60fluid-bed drier with an inlet air temperature setting of about 70° C.+5°C. The unit is dried until a moisture level of <1.0% is obtained asdetermined using a Computrac® Moisture Analyzer, model MA5A. The driedgranulation is discharged into appropriately labeled, doublepolyethylene-lined drums and reconciled.

[0096] The dried and reconciled granulation is passed through a KemutecBetaGrind mill equipped with a 1.5 mm screen and running atapproximately 1500 RPM. The milled granulation is collected intoappropriately labeled, double polyethylene-lined drums and reconciled.The milled granulation is sampled and tested by Quality Control andreleased prior to further processing.

[0097] The released granulation units are charged to a Patterson-Kelley20 ft3 V-blender after which they are blended together for about 10±1minutes and then discharged to appropriately labeled, doublepolyethylene-lined containers.

[0098] As stated above, Niaspan® tablets are formulated from a commongranulation which is blended with appropriate quantities of Methocel,USP E10M Premium CR Grade and Stearic Acid, NF to achieve the finaldosage formulation. Tables IA and IB describe the formulation for eachNiaspan® tablet strength, 375 mg, 500 mg, 750 mg and 1000 mg,respectively.

[0099] Two study groups consisting of eleven and fourteen patients eachwere formed. Blood samples were taken from the patients, and tested fortotal cholesterol, LDL cholesterol, triglycerides and HDL cholesterol toestablish baseline levels from which fluctuations in these lipids couldbe compared. The patients were then placed upon a regiment of the abovediscussed tablets, totaling approximately 1500 mg of nicotinic acid,once per day before going to bed. After eight weeks of this regimen, thepatients were again tested for lipid profiles. The results of testsconducted at eight weeks, showing the changes in the lipid profiles as apercentage change from the baseline, are reported in the tablehereinbelow. Positive numbers reflect percentage increases and negativenumbers reflect percentage decreases in this table. TABLE II PatientStudy Lipid Profile Data Pt. No. Total-C LDL-C Apo B Trigs HDL-C HDL,-CLp(a) GROUP A 1 −8.2 −12.0 NA −17.3 22.0 NA NA 2 −5.9 −27.0 NA −28.765.0 NA NA 3 −15.1 −13.0 NA −22.0 −9.1 NA NA 4 −3.3 −10.0 NA 61.6 3.8 NANA 5 −16.5 −17.7 NA −28.8 11.1 NA NA 6 −12. −25.9 NA −42.0 51.6 NA NA 7−24.2 −31.4 NA −30.4 12.5 NA NA 8 −6.7 −7.4 NA −42.4 18.8 NA NA 9 4.51.1 NA 7.2 9.2 NA NA 10  2.8 −0.2 NA −2.7 22.9 NA NA 11  −13.0 −9.4 NA−54.0 44.3 NA NA Mean −8.9 −9.4 NA −18.9 23.0 NA NA p-Value 0.0004-8.90.0001- 0.0371 0.0068 13.9 GROUP B 1 −19.2 −27.1 −24.4 −33.4 20.0 22.3−81.9 2 −32.2 −35.7 −28.0 −60.4 4.3 3.2 −25.3 3 −21.4 −33.6 −35.6 −33.430.4 38.6 −17.4 4 −19.9 −24.6 −15.1 −20.8 9.6 16.1 −27.0 5 −3.3 −2.1−29.4 −41.1 5.8 2.4 −22.4 6 PATIENT WITHDREW FROM STUDY 7 23.1 −32.6−42.6 −58.6 49.2 68.9 −14.3 8 24.8 34.0 −28.4 5.5 6.5 −6.8 Na 9 10.112.0 −16.8 −11.6 2−.7 −12.3 40.6 10  −2.9 −7.7 −28.0 −59.0 53.1 70.5−41.2 11  −10.5 −18.8 −25.3 −53.4 31.8 39.7 NA 12  −20.0 −30.8 −30.411.7 21.1 25.0 −28.4 13  17.4 16.8 −17.5 −17.5 51.3 51.9 38.5 14  −9.4−16.6 −32.0 −46.9 52.3 67.6 17.6 MEAN −8.7 −12.8 −32.2 −27.2 25.3 30.1−17.9 p-Value 0.0002 <0.0001 0.0001 <0.001 <0.0001 0.0002 <0.0199Combined −8.7 −13.3 Gp B −26.1 25.3 Gp B Gp B p-Value 0.0002 <0.0001only <.0001 <0.0001 only only

[0100] The data reported in Table II shows that the LDL levels in theGroup A patients had a mean decrease of −13.9% and triglyceride decreaseof −18.9% HDL cholesterol levels, the beneficial cholesterol, wereraised by 23.0% in this Group. Similar results were obtained with theGroup B patients. These studies demonstrate that dosing the sustainedrelease formulation during the evening hours or at night providesreductions in LDL cholesterol levels equal to immediate release niacinon a milligram per milligram basis, but superior reductions intriglyceride reduction when compared to sustained release formulationsdosed during daytime hours on a milligram per milligram basis.Additionally, the increases in HDL cholesterol obtained from doing thesustained release formulation during the evening or at night were ±23.0%for one group and ±25.3% for the other group. Dosing during the eveningtherefore provides reduction in LDL cholesterol plus significantdecreases in triglycerides and increases in HDL cholesterol withonce-a-day dosing.

[0101] Groups A and B were also tested for liver enzymes (AST, ALT andAlkaline Phosphatase), uric acid and fasting glucose levels at the startof the study described hereinabove (to form a baseline) and at two, fourand eight week intervals. The results of these tests are listed inTABLES III-VII hereinbelow. TABLE III THE EFFECT OF NIASPAN ® THERAPY ONAST (SGOT) LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28)Weeks of Therapy With Niaspan ® Reference Pt# Baseline 2 Wks. 4 Wks. 8Wks. Range GROUP A  1 28 29 25 24 0-50  2 24 25 24 26 0-50  3 17 18 2221 0-50  4 14 16 15 17 0-50  5 22 NA 32 52 0-50  6 21 17 17 14 0-50  717 17 14 18 0-50  8 20 21 22 22 0-50  9 16 16 17 20 0-50 10 18 21 21 250-50 11 21 21 22 21 0-50 GROUP B  1 23 25 38 33 0-50  2 20 20 21 21 0-50 3 15 20 18 19 0-50  4 28 22 28 26 0-52  5 23 21 17 18 0-50  6 PATIENTWITHDREW DUE TO FLUSHING  7 21 18 18 19 0-50  8 18 19 18 19 0-50  9 1516 18 15 0-50 10 16 15 19 28 0-50 11 20 22 24 28 0-50 12 23 25 28 220-50 13 20 15 20 19 0-50 14 18 25 20 18 0-50 Combined Mean 19.8 20.420.8 21.1 Change From +3.0% +5.1% +6.6% Baseline

[0102] TABLE IV THE EFFECT OF NIASPAN ® THERAPY ON ALT (SGPT) LEVELS(U/L) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of TherapyWith Niaspan ® Reference Pt# Baseline 2 Wks. 4 Wks. 8 Wks. Range GROUP A 1 32 28 39 30 0-55  2 24 25 23 26 0-55  3 18 23 30 30 0-55  4 7 13 1414 0-55  5 14 NA 43 46 0-55  6 22 11 14 10 0-55  7 9 7 11 7 0-55  8 1618 23 21 0-55  9 14 17 20 14 0-55 10 14 15 17 19 0-55 11 18 18 20 160-55 GROUP B  1 16 17 27 29 0-55  2 16 14 15 22 0-55  3 13 21 13 16 0-55 4 23 20 26 17 0-55  5 21 23 17 15 0-55  6 PATIENT WITHDREW DUE TOFLUSHING  7 21 16 18 21 0-55  8 18 20 17 18 0-55  9 11 5 11 8 0-55 10 810 14 17 0-55 11 17 12 18 16 0-55 12 14 18 20 16 0-55 13 14 NA 11 100-55 14 23 23 19 19 0-55 Combined Mean 17.7 17.5 19.3 18.2 Change −1.1%9.0% +2.8% From Baseline

[0103] TABLE V THE EFFECT OF NIASPAN ® THERAPY ON ALKALINE PHOSPHATASELEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28) Weeks ofTherapy With Niaspan ® Reference Pt# Baseline 2 Wks. 4 Wks. 8 Wks. RangeGROUP A  1 52 56 57 55 20-140  2 103 100 89 102 20-140  3 54 45 53 5120-140  4 70 68 71 91 20-140  5 77 NA 74 81 20-140  6 55 48 49 51 20-140 7 72 71 79 75 20-140  8 55 49 47 50 20-140  9 53 55 56 45 20-140 10 7473 75 75 20-140 11 18 18 20 16 20-140 GROUP B  1 73 67 89 95 20-140  282 64 72 71 20-140  3 73 69 81 82 20-140  4 37 36 37 38 20-140  5 65 5354 61 20-140  6 PATIENT WITHDREW DUE TO FLUSHING  7 64 58 58 58 20-140 8 79 78 65 73 20-140  9 94 92 103 93 20-140 10 69 67 70 65 20-140 11 5967 63 72 20-140 12 65 59 59 63 20-140 13 64 68 66 64 20-140 14 72 61 5964 20-140 Combined Mean 66.5 61.5 63.3 65.8 Change −6.1% −3.4% +0.005%From Baseline

[0104] TABLE VI THE EFFECT OF NIASPAN ® THERAPY ON URIC ACID LEVELS(mg/dL) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of TherapyWith Niaspan ® Reference Pt# Baseline 2 Wks. 4 Wks. 8 Wks. Range GROUP A 1 5.2 5.0 4.8 4.3 4.0-8.5  2 4.0 4.6 4.5 6.2 2.5-7.5  3 6.3 7.0 6.5 6.24.0-8.5  4 3.1 4.6 4.2 3.8 2.5-7.5  5 3.4 NA 3.3 4.2 2.5-7.5  6 6.6 5.55.6 4.7 4.0-8.5  7 3.8 4.5 4.3 4.9 2.5-7.5  8 4.4 3.8 5.1 4.5 2.5-7.5  93.9 4.5 4.6 3.5 2.5-7.5 10 2.6 2.9 2.8 2.7 2.5-7.5 11 4.7 5.5 5.2 5.32.5-7.5 GROUP B  1 3.7 4.2 4.7 3.5 2.5-7.5  2 2.8 3.5 3.6 2.3 4.0-8.5  34.2 5.3 5.5 5.3 2.5-7.5  4 4.7 3.9 5.1 3.6 4.0-8.5  5 3.7 4.1 4.1 3.82.5-7.5  6 PATIENT WITHDREW DUE TO FLUSHING  7 5.8 6.6 6.6 6.8 2.5-7.5 8 4.7 4.3 5.4 5.6 2.5-7.5  9 3.7 4.6 5.1 3.8 2.5-7.5 10 4.2 5.0 4.4 8.52.5-7.5 11 1.9 3.0 2.8 5.0 2.5-7.5 12 5.6 5.4 6.2 5.6 4.0-8.5 13 4.2 4.64.6 5.3 2.5-7.5 14 5.5 5.4 6.1 5.3 2.5-7.5 Combined 4.54 4.82 4.92 4.86*p = 0.3450 Mean Change +6.2% +8.4% +7.0% From Baseline

[0105] TABLE VII THE EFFECT OF NIASPAN ® THERAPY ON FASTING GLUCOSELEVELS (mg/dL) (1500 mgs dosed once-a-day at night) (n = 28) Weeks ofTherapy With Niaspan ® Reference Pt# Baseline 2 Wks. 4 Wks. 8 Wks. RangeGROUP A  1 114 122 123 110 70-115  2 101 105 107 101 80-125  3 99 98 103103 70-115  4 100 118 94 94 80-12580-12  5 89 NA 82 103 80-125  6 97 10394 107 70-115  7 85 107 100 94 80-125  8 98 107 103 101 80-125  9 97 97100 110 80-125 10 94 101 111 97 70-115 11 102 103 95 95 80-125 GROUP B 1 101 97 83 99 70-115  2 90 95 96 89 80-125  3 96 98 95 97 70-115  4116 139 113 125 80-125  5 88 98 91 95 70-115  6 PATIENT WITHDREW DUE TOFLUSHING  7 106 114 118 117 70-115  8 95 106 106 108 70-115  9 81 92 8492 70-115 10 108 117 122 105 70-115 11 85 106 106 108 70-115 12 92 89101 86 80-125 13 99 105 94 100 70-125 14 100 108 84 197 70-125 Combined98.4 105.8 101.6 102.3 Mean Change From +7.5% +3.3% +4.0% Baseline

[0106] In order to provide a comparison between the state of the artprior to the present invention, and in order to quantify the magnitudeof the improvement that the invention provides over the prior art,another study was conducted. This study included 240 patients dosedaccording to the present invention as described hereinabove. Compared tothis group was the group of patients studied by McKenney et al., asreported hereinabove. The results of this study are reported in TABLEVIII hereinbelow. TABLE VIII A Comparison of Changes in Liver FunctionTests DOSE 0 500 1000 1500 2000 2500 3000 TOTAL McKenney Sr^(b)Niacin^(a) AST 23.8 27.9 40.4 36.6 56.5 NA 97.0 % — 117 170 154 237 NA408 Invention Dosage^(c) AST 24.3 NA 23.7 17.5 26.6 27.6 27.8 % — NA 9811398 109113 114 114 McKenney SR Niacin ALT 25.6 29.5 36.3 39.0 59.1 NA100.0 % — 115 142 152 231 NA 391 Invention Dosage ALT 21.4 NA 18.7 22.621.3 22.4 21.8 % — NA 87 106 100 105 102 McKenney SR Niacin ALK 95   95106 105 136 NA 135 % — 100 112 111 143 NA 142 Invention Dosage ALK 74.7NA 73.9 76.1 73.4 76.7 78.0 % — NA 99 102 98 103 104 McKenney SR NiacinDrop — 0 2 2 7 NA 7 18 N — — — — — — — 23 % — 0 9 9 30 NA 30 78Invention Dosage Drop — — 0 0 0 0 0  0 n — — 26 67 97 35 15 240  % — — 00 0 0 0  0 1 — — 15 46 77 31 15 184  year 1 — — 58 69 79 89 100 77 year

[0107] The results of the comparison of the studies reported in TableVIII show that the control group (the McKenney group) had 18 of 23, or78 percent of the patients therein drop out of the test because of anincrease in their respective liver function tests. The patients withdrewat the direction of the investigator. In comparison, a group of 240patients treated according to the present invention had zero patientsdrop out, based upon the same criteria for withdrawal. The test resultsreported above indicate that this sustained release dosage form causedno elevation in liver function tests (i.e., no liver damage), noelevations in uric acid and only a small, 7.5% increase in fastingglucose levels which in fact decreased during continued therapy.

[0108] Thus it should be evident that the compositions and method of thepresent invention are highly effective in controlling hyperlipidemia inhyperlipidemics, by reducing the levels of LDL cholesterol, triglycerideand Lp(a) while increasing HDL cholesterol levels. The present inventionis also demonstrated not to cause elevations in liver function tests,uric acid or glucose levels for the hyperlipidemics.

[0109] Based upon the foregoing disclosure, it should now be apparentthat the use of the compositions and methods described herein will carryout the objects set forth hereinabove. It is, therefore, to beunderstood that any variations in sustained release formulation evidentfall within the scope of the claimed invention and thus, the selectionof specific component elements can be determined without departing fromthe spirit of the invention herein disclosed and described. Inparticular, sustained release excipients, binders and processing aidsaccording to the present invention are not necessarily limited to thoseexemplified hereinabove. Thus, the scope of the invention shall includeall modifications and variations that may fall within the scope of theattached claims.

Having described my invention, I claim:
 1. An intermediate releasenicotinic acid formulation suitable for oral administration once-a-dayas a single dose for treating hyperlipidemia without causingdrug-induced hepatotoxicity to a level which would require use of saidintermediate release nicotinic acid formulation to be discontinued, saidintermediate release nicotinic acid formulation having: a dissolutioncurve similarity fit factor F₂ of at least about 79; and an in vitrodissolution profile, when measured in a type I dissolution apparatus(basket), according to U.S. Pharmacopeia XXII, at about 37° C. indeionized water at about 100 rpm, as follows: (a) less than about 15% ofthe nicotinic acid is released after about 1 hour in the apparatus; (b)between about 15% and about 30% of the nicotinic acid is released afterabout 3 hours in the apparatus; (c) between about 30% and about 45% ofthe nicotinic acid is released after about 6 hours in the apparatus; (d)between about 40% and about 60% of the nicotinic acid is released afterabout 9 hours in the apparatus; (e) between about 50% and about 75% ofthe nicotinic acid is released after about 12 hours in the apparatus;and (f) at least about 75% is released after about 20 hours in theapparatus.
 2. An intermediate release nicotinic acid formulation ofclaim 1 , wherein approximately 100% of the nicotinic acid is releasedafter about 20 hours in the apparatus.
 3. An intermediate releasenicotinic acid formulation of claim 1 , wherein said nicotinic acidformulation is a tablet.
 4. An intermediate release nicotinic acidformulation of claim 3 , wherein said tablet contains nicotinic acid inan amount selected from the group consisting of about 375 mg, about 500mg and about 750 mg.
 5. An intermediate release nicotinic acidformulation of claim 1 , wherein said in vitro dissolution profile is asfollows: (a) between about 9.6% and about 13.8% of the nicotinic acid isreleased after about 1 hour in the apparatus; (b) between about 21.2%and about 27.8% of the nicotinic acid is released after about 3 hours inthe apparatus; (c) between about 35.1% and about 44.2% of the nicotinicacid is released after about 6 hours in the apparatus; (d) between about45.6% and about 58.5% of the nicotinic acid is released after about 9hours in the apparatus; (e) between about 56.2% and about 72% of thenicotinic acid is released after about 12 hours in the apparatus; and(f) at least about 75% is released after about 20 hours in theapparatus.
 6. An intermediate release nicotinic acid formulation ofclaim 5 , wherein approximately 100% of the nicotinic acid is releasedafter about 20 hours in the apparatus.
 7. An intermediate releasenicotinic acid formulation of claim 5 , wherein said nicotinic acidformulation is a tablet.
 8. An intermediate release nicotinic acidformulation of claim 7 , wherein said tablet contains nicotinic acid inan amount selected from the group consisting of about 375 mg, about 500mg and about 750 mg.
 9. An intermediate release nicotinic acidformulation of claim 1 , wherein said in vitro dissolution profile is asfollows: (a) between about 9.6% and about 13.8% of the nicotinic acid isreleased after about 1 hour in the apparatus; (b) between about 21.2%and about 27.8% of the nicotinic acid is released after about 3 hours inthe apparatus; (c) between about 35.1% and about 44.2% of the nicotinicacid is released after about 6 hours in the apparatus; (d) between about45.6% and about 58.5% of the nicotinic acid is released after about 9hours in the apparatus; (e) between about 56.2% and about 72% of thenicotinic acid is released after about 12 hours in the apparatus; and(f) at least about 75% is released after about 20 hours in theapparatus.
 10. An intermediate release nicotinic acid formulation ofclaim 9 , wherein approximately 100% of the nicotinic acid is releasedafter about 20 hours in the apparatus.
 11. An intermediate releasenicotinic acid formulation of claim 9 , wherein said nicotinic acidformulation is a tablet.
 12. An intermediate release nicotinic acidformulation of claim 11 , wherein said tablet contains nicotinic acid inan amount selected from the group consisting of about 375 mg, about 500mg and about 750 mg.
 13. An intermediate release nicotinic acidformulation suitable for oral administration once-a-day as a single dosefor treating hyperlipidemia without causing drug-induced hepatotoxicityto a level which would require use of said intermediate releasenicotinic acid formulation to be discontinued, said intermediate releasenicotinic acid formulation containing at least about 1000 mg ofnicotinic acid and having: a dissolution curve similarity fit factor F₂of at least about 44; and an in vitro dissolution profile, when measuredin a type I dissolution apparatus (basket), according to U.S.Pharmacopeia XXII, at about 37° C. in deionized water at about 100 rpm,as follows: (a) less than about 15% of the nicotinic acid is releasedafter about 1 hour in the apparatus; (b) between about 15% and about 30%of the nicotinic acid is released after about 3 hours in the apparatus;(c) between about 30% and about 45% of the nicotinic acid is releasedafter about 6 hours in the apparatus; (d) between about 40% and about60% of the nicotinic acid is released after about 9 hours in theapparatus; (e) between about 50% and about 75% of the nicotinic acid isreleased after about 12 hours in the apparatus; and (f) at least about75% is released after about 20 hours in the apparatus.
 14. Anintermediate release nicotinic acid formulation of claim 13 , whereinapproximately 100% of the nicotinic acid is released after about 20hours in the apparatus.
 15. An intermediate release nicotinic acidformulation of claim 13 , wherein said nicotinic acid formulation is atablet.
 16. An intermediate release nicotinic acid formulation of claim13 , wherein said in vitro dissolution profile is as follows: (a)between about 9.6% and about 13.8% of the nicotinic acid is releasedafter about 1 hour in the apparatus; (b) between about 21.2% and about27.8% of the nicotinic acid is released after about 3 hours in theapparatus; (c) between about 35.1% and about 44.2% of the nicotinic acidis released after about 6 hours in the apparatus; (d) between about45.6% and about 58.5% of the nicotinic acid is released after about 9hours in the apparatus; (e) between about 56.2% and about 72% of thenicotinic acid is released after about 12 hours in the apparatus; and(f) at least about 75% is released after about 20 hours in theapparatus.
 17. An intermediate release nicotinic acid formulation ofclaim 16 , wherein approximately 100% of the nicotinic acid is releasedafter about 20 hours in the apparatus.
 18. An intermediate releasenicotinic acid formulation of claim 16 , wherein said nicotinic acidformulation is a tablet.
 19. An intermediate release nicotinic acidformulation of claim 1 , wherein said in vitro dissolution profile is asfollows: (a) between about 9.6% and about 13.8% of the nicotinic acid isreleased after about 1 hour in the apparatus; (b) between about 21.2%and about 27.8% of the nicotinic acid is released after about 3 hours inthe apparatus; (c) between about 35.1% and about 44.2% of the nicotinicacid is released after about 6 hours in the apparatus; (d) between about45.6% and about 58.5% of the nicotinic acid is released after about 9hours in the apparatus; (e) between about 56.2% and about 72% of thenicotinic acid is released after about 12 hours in the apparatus; and(f) at least about 75% is released after about 20 hours in theapparatus.
 20. An intermediate release nicotinic acid formulation ofclaim 19 , wherein approximately 100% of the nicotinic acid is releasedafter about 20 hours in the apparatus.
 21. An intermediate releasenicotinic acid formulation of claim 19 , wherein said nicotinic acidformulation is a tablet.